Dense Genotyping of Immune-Related Loci Implicates Host Responses to Microbial Exposure in Behcets Disease Many of the details of this study have been summarized in last years report. Briefly, we analyzed 1900 Turkish Behcets disease cases and 1779 controls using an Illumina iSelect Custom Array, the Immunochip. The most significantly associated single nucleotide polymorphism (SNP) was rs1050502, a synonymous variant of HLA-B and a tag SNP for HLA-B*51. In the Turkish discovery set, we identified 3 novel loci, IL1A-IL1B, IRF8, and CEBPB-PTPN1, with genome-wide significance (P < 5 x 10e-08) by direct genotyping, and ADO-EGR2 by imputation. ADO-EGR2, IRF8, and CEBPB-PTPN1 replicated by genotyping 982 Iranian cases and 826 controls. Imputed data on 608 Japanese cases and 737 controls replicated ADO-EGR2 and IRF8 and additionally identified RIPK2 and LACC1 with genome-wide significance. The disease-associated allele of rs4402765, the lead marker of the IL1A-IL1B locus, was associated with both decreased IL-1alpha and increased IL-1beta production in vitro by peripheral blood mononuclear cells. FUT2 non-secretor genotypes of the ancestry-specific SNPs, rs601338 (Turkish and Iranian) and rs1047781 (Japanese), showed strong disease association (P = 5.89 x 10e-15). Our findings extend shared susceptibility genes with Crohns disease and leprosy, and implicate mucosal factors and the innate immune response to microbial exposure in Behcets disease susceptibility. A manuscript describing these findings in detail is currently under re-review. Analysis of ER-Associated Aminopeptidase 1 (ERAP1) Protein Structural Variants and Their Association with Behcets Disease The ERAP1 protein is responsible for trimming intracellular proteasome-derived peptides for efficient loading and presentation by HLA class I proteins. A coding ERAP1 variant (p.Arg725Gln) is recessively associated with Behcets disease. The same variant is protective for two other HLA class I-associated diseases, ankylosing spondylitis and psoriasis. The ERAP1 association is limited to individuals who carry the disease-associated HLA type in all 3 diseases. The ERAP1 protein is highly polymorphic with 10 missense amino acid variants with frequency greater than 1% found in the 1000 Genomes Project EUR super-population. A single disease-associated variant amino acid does not act in isolation, but acts instead in the context of all the variants present in the complete protein structure. We therefore used haplotype analysis to identify the common protein allotypes of ERAP1 and to evaluate their contributions to the risk of Behcets disease. We identified 10 haplotypes with frequency greater than 1% in the EUR population. Eight of the 10 haplotypes were found at greater than 1% in the Turkish population and only one, Hap10 (bearing 5 non-ancestral alleles, M349V, K528R, D575N, R725Q, and Q730E) was recessively associated with disease in 1900 cases and 1779 controls (P = 3.13 x 10e-6). In the Turkish population, individuals who carry HLA-B*51 and are homozygous for the Hap10 haplotype have a 10.96 fold increased disease risk compared with those with neither risk factor (P = 4.8 x 10e-20). This ERAP1 allotype has poor peptide trimming activity. Thus, it is likely to contribute to Behcets disease risk by influencing the nature of the peptide pool available for binding HLA-B*51. A paper describing these findings was published in the Annals of Rheumatic Diseases.